WO1992012161A1 - Novel pyrimido-benzothiazines - Google Patents
Novel pyrimido-benzothiazines Download PDFInfo
- Publication number
- WO1992012161A1 WO1992012161A1 PCT/US1991/009161 US9109161W WO9212161A1 WO 1992012161 A1 WO1992012161 A1 WO 1992012161A1 US 9109161 W US9109161 W US 9109161W WO 9212161 A1 WO9212161 A1 WO 9212161A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- pharmaceutically
- alkyl
- acceptable salt
- Prior art date
Links
- 0 CC1OC1NC=C(C(*)=O)O Chemical compound CC1OC1NC=C(C(*)=O)O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- This invention relates to novel pyrimido-benzothiazine derivative compounds.
- the compounds of the present inven- tion inhibit the action of the lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals.
- This invention also relates to pharmaceutical compositions comprising such compounds.
- Arachidonic acid is known to be the biological precur ⁇ sor of several groups of endogenous metabolites, prosta- glandins including prostacyclins, thromboxanes and leuko- trienes.
- the first step of arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids via the action of phospholipase. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and throm ⁇ boxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes.
- Leukotrienes have been implicated in the pathophysiology of inflammatory diseases including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflamma ⁇ tory bowel disease. Compounds that inhibit lipoxygenase are expected to provide significant new therapy for both acute and chronic inflammatory conditions.
- X is, inter alia. S, SO or S0 2 ;
- R l is, inter alia, H or (C -C alkyl;
- R 2 , R 3 , R 4 and R 5 are inter alia, independent ⁇ ly H, (Cj-C 6 )alkyl, (C j -Cg)alkenyl or - (CE 2 )__ti where n is 0-6 and M is halogen or various groups and T is H or OR 15 where R 15 is H or various groups are disclosed in EP 138481, published April 24, 1985 and corresponding to JP 60155165, as leukotriene biosynthesis inhibitors useful in treating allergic conditions, asthma, cardiovascular disorders, inflammation and certain skin diseases.
- R 1 is hydrogen or (C 1 -C 6 )alkyl
- R 2 is hydrogen, halogen
- R 3 is hydrogen or (Cj-Cg)alkyl
- R 4 is hydrogen, (Ci-Cg)alkyl, (C 3 - C g )cycloalkyl, (Cj-Cg) alkyl or aryl-f -Cg)alkyl; provided that in formula (I), R 1 , R 2 , R 3 and R 4 are not simultaneously hydrogen, R 2 , R 3 and R 4 are not simultaneously hydrogen when R 1 is methyl and R 2 and R 3 are not simulta ⁇ neously hydrogen when R 1 and R 4 are respectively methyl; provided further that in formula (II) , R 1 , R 2 and R 3 are not simultaneously hydrogen and R 2 and R 3 are not simultaneously hydrogen when R 1 is methyl; and provided further still that the groups R 2 and R 3 may be attached to any available position on the ring in formula (I) or
- a preferred group of compounds comprises compounds of formula (I) wherein R 1 is (Cj-C 6 )alkyl. Also preferred are compounds of formula (I) wherein R 1 is methyl and R 2 is halogen, (Cj-Cg)alkyl or (Cj-Cg)alkoxy. Another preferred group of compounds comprises compounds of formula (II) wherein R 1 is (Cj-Cg)alkyl. Also preferred are compounds of formula (II) wherein R 1 is methyl and R 2 is halogen, (C_- C 6 )alkyl, (Cj-Cg)alkoxy or alkyl.
- halogen is used to mean radicals derived from the elements fluorine, chlorine, bromine and iodine
- alkyl is used to mean straight or branched chain radicals, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl and the like
- alkoxy is used to mean -OR 5 wherein R j is an alkyl radical, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like
- halosubstituted alkyl refers to an alkyl radical as described above substituted with one or more halogens, including, but not limited to chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl and the like
- alkoxyalkyl is used to mean -
- the pharmaceutically-acceptable acid salts are those formed from acids which yield non-toxic acid salts, for example, hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, and formate salts.
- compositions for treatment of inflammatory diseases, allergy and cardiovascu ⁇ lar diseases in a mammal which comprises a pharmaceutically- acceptable carrier or diluent and a compound of the above formula (I) or (II) or a pharmaceutically-acceptable salt thereof.
- This invention further includes methods for treating inflammatory diseases, allergy and cardiovascular diseases in a mammal which comprise administering to said mammal an effective amount of a compound of the above formula (I) or
- bromine is added dropwise to an ice-cooled solution or suspension of a pyrimidine-2,4(lH,3H)-dione derivative of formula (III) in water until the solution or suspension is colored pale yellow.
- the pyrimidine-2,4(lH,3H)-dione derivatives of formula (III) are prepared, for example, by the methods described in Heterocyclic Compounds 16.
- To the resulting pale yellow solution or suspen- sion is added carefully an ice cold saturated aqueous NaHC0 3 solution.
- the pharmaceutically-acceptable salts of the compounds of the present invention are readily prepared by contacting said compounds with a stoichiometric amount of, in the case of non-toxic cation, an appropriate metal hydroxide or alkoxide or amine in either aqueous solution or a suitable organic solvent; or, in the case of a non-toxic acid salt, an appropriate mineral or organic acid in either aqueous solution or a suitable organic solvent.
- the respective salt may then be obtained by precipitation or by evaporation of the solvent.
- the compounds of this invention inhibit the activity of the lipoxygenase enzyme. This inhibition has been demon ⁇ strated by an assay using rat peritoneal cavity resident cells which determines the effect of said compounds on the metabolism of arachidonic acid as described in Jap. J. Inflammation 7:145-150, 1987, "Synthesis of leukotrienes by peritoneal macrophages".
- the compounds of the present invention make them useful for controlling the symptoms induced by the endogenous metabo ⁇ lites arising from arachidonic acid in a mammalian subject.
- the compounds therefore are valuable in the prevention and treatment of disease states in which the accumulation of arachidonic acid metabolites are the causative factor, e.g., allergic bronchial asthma, skin disorders, rheumatoid arthritis, osteoarthritis and thrombosis.
- the compounds of formula (I) and (II) , and their pharmaceutically-acceptable salts are of particular use in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in a human subject as well as in the inhibition of the lipoxygenase enzyme.
- the compounds of this invention and their pharmaceu- tically-acceptable salts can be administered to a human subject either alone, or, preferably, in combination with pharmaceutically-acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceu ⁇ tical practice.
- a compound of this invention can be administered by a variety of conventional routes of adminis ⁇ tration including oral and parenteral administration and by inhalation.
- the dose range will be from about 0.1 to 20 mg/kg body weight of the subject to be treated per day, preferably from about 0.1 to 1.0 mg/kg per day in single or divided doses.
- an effective dose will be from 0.1 to 1.0 mg/kg body weight of the subject to be treated per day. In some instances it may be necessary to use dosages outside these limits, since the dosage will necessarily vary according to the age, weight and response of the individual patient as well as the severity of the patient's symptoms and the potency of the particular compound being administered.
- the compounds of the invention and their pharmaceutically-acceptable salts can be adminis ⁇ tered, for example, in the form of tablets, powders, lozenges, syrups or capsules, or as an aqueous solution or suspension.
- carriers which are commonly used include lactose and corn starch.
- lubricating agents such as magnesium stearate, are commonly added.
- useful diluents are lactose and dried corn starch.
- aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added.
- a sterile solutio of the active ingredient is pre- pared, and the pH of the solutions should be suitably adjusted and buffered.
- the total concentration of solutes should be controlled to make the preparation isotonic.
- the present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples.
- Proton nuclear magnetic resonance spectra (NMR) were measured at 270 MHz unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/078,315 US5418231A (en) | 1991-01-07 | 1991-12-16 | Pyrimido-benzothiazines |
EP92901466A EP0566592B1 (en) | 1991-01-07 | 1991-12-16 | Pyrimido-benzothiazines with lipoxygenase inhibitory action |
DE69104067T DE69104067T2 (en) | 1991-01-07 | 1991-12-16 | Pyrimido-benzothiazine with lipoxygenase inhibition. |
FI933102A FI933102A (en) | 1991-01-07 | 1993-07-06 | NYA PYRIMIDOBENSOTIAZINER |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3000159A JPH0739422B2 (en) | 1991-01-07 | 1991-01-07 | Novel pyrimido-benzothiazines and compositions |
JP3/159 | 1991-01-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992012161A1 true WO1992012161A1 (en) | 1992-07-23 |
Family
ID=11466261
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/009161 WO1992012161A1 (en) | 1991-01-07 | 1991-12-16 | Novel pyrimido-benzothiazines |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP0566592B1 (en) |
JP (1) | JPH0739422B2 (en) |
AT (1) | ATE111469T1 (en) |
CA (1) | CA2099558A1 (en) |
DE (1) | DE69104067T2 (en) |
DK (1) | DK0566592T3 (en) |
ES (1) | ES2059209T3 (en) |
FI (1) | FI933102A (en) |
IE (1) | IE64069B1 (en) |
PT (1) | PT99979A (en) |
WO (1) | WO1992012161A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1695595A1 (en) * | 1966-11-08 | 1972-01-20 | Pfizer | Process for the preparation of 1,2,3,4-tetrahydro-4a (H) -pyrimido- [5,4-b] [1,4] -benzothiazine-2,4-diones |
US4845083A (en) * | 1983-10-05 | 1989-07-04 | Merck Frosst Canada, Inc. | Method of inhibiting mammalian leukotriene biosynthesis |
-
1991
- 1991-01-07 JP JP3000159A patent/JPH0739422B2/en not_active Expired - Lifetime
- 1991-12-16 AT AT92901466T patent/ATE111469T1/en not_active IP Right Cessation
- 1991-12-16 EP EP92901466A patent/EP0566592B1/en not_active Expired - Lifetime
- 1991-12-16 CA CA002099558A patent/CA2099558A1/en not_active Abandoned
- 1991-12-16 DK DK92901466.0T patent/DK0566592T3/en active
- 1991-12-16 WO PCT/US1991/009161 patent/WO1992012161A1/en active IP Right Grant
- 1991-12-16 DE DE69104067T patent/DE69104067T2/en not_active Expired - Fee Related
- 1991-12-16 ES ES92901466T patent/ES2059209T3/en not_active Expired - Lifetime
-
1992
- 1992-01-06 IE IE920028A patent/IE64069B1/en not_active IP Right Cessation
- 1992-01-06 PT PT99979A patent/PT99979A/en not_active Application Discontinuation
-
1993
- 1993-07-06 FI FI933102A patent/FI933102A/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1695595A1 (en) * | 1966-11-08 | 1972-01-20 | Pfizer | Process for the preparation of 1,2,3,4-tetrahydro-4a (H) -pyrimido- [5,4-b] [1,4] -benzothiazine-2,4-diones |
US4845083A (en) * | 1983-10-05 | 1989-07-04 | Merck Frosst Canada, Inc. | Method of inhibiting mammalian leukotriene biosynthesis |
Also Published As
Publication number | Publication date |
---|---|
JPH04230690A (en) | 1992-08-19 |
PT99979A (en) | 1993-01-29 |
DE69104067T2 (en) | 1995-02-02 |
ATE111469T1 (en) | 1994-09-15 |
IE920028A1 (en) | 1992-07-15 |
FI933102A0 (en) | 1993-07-06 |
DK0566592T3 (en) | 1994-10-17 |
DE69104067D1 (en) | 1994-10-20 |
EP0566592B1 (en) | 1994-09-14 |
JPH0739422B2 (en) | 1995-05-01 |
EP0566592A1 (en) | 1993-10-27 |
ES2059209T3 (en) | 1994-11-01 |
FI933102A (en) | 1993-07-06 |
CA2099558A1 (en) | 1992-07-08 |
IE64069B1 (en) | 1995-07-12 |
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